Abstract

Background

This is an updated version of the original Cochrane review published in Issue 3, 2006, which included 23 trials. The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long‐term profile of benefits and risks for people with neuropathic pain.

Objectives

To reassess the efficacy and safety of opioid agonists for the treatment of neuropathic pain.

Search methods

We searched CENTRAL, on The Cochrane Library (Issue 10 of 12, 2012), MEDLINE (1966 to Oct week 3, 2012), and EMBASE (1980 to 2012, week 42) for articles in any language, and reference lists of reviews and retrieved articles. Searches were originally run in 2005, then again in 2010 and 2012.

Selection criteria

We included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Pain was assessed using validated instruments, and adverse events were reported. We excluded studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally.

Data collection and analysis

Two review authors independently extracted data and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.

Main results

Thirty‐one trials met our inclusion criteria, studying 10 different opioids: 23 studies from the original 2006 review and eight additional studies from this updated review.

Seventeen studies (392 participants with neuropathic pain, average 22 participants per study) provided efficacy data for acute exposure to opioids over less than 24 hours. Sixteen reported pain outcomes, with contradictory results; 8/16 reported less pain with opioids than placebo, 2/16 reported that some but not all participants benefited, 5/16 reported no difference, and 1/16 reported equivocal results. Six studies with about 170 participants indicated that mean pain scores with opioid were about 15/100 points less than placebo.

Fourteen studies (845 participants, average 60 participants per study) were of intermediate duration lasting 12 weeks or less; most studies lasted less than six weeks. Most studies used imputation methods for participant withdrawal known to be associated with considerable bias; none used a method known not to be associated with bias. The evidence, therefore, derives from studies predominantly with features likely to overestimate treatment effects, i.e. small size, short duration, and potentially inadequate handling of dropouts. All demonstrated opioid efficacy for spontaneous neuropathic pain. Meta‐analysis demonstrated at least 33% pain relief in 57% of participants receiving an opioid versus 34% of those receiving placebo. The overall point estimate of risk difference was 0.25 (95% confidence interval (CI) 0.13 to 0.37, P < 0.0001), translating to a number needed to treat for an additional beneficial outcome (NNTB) of 4.0 (95% CI 2.7 to 7.7). When the number of participants achieving at least 50% pain relief was analyzed, the overall point estimate of risk difference between opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02 to 0.33, P = 0.03), translating to an NNTB of 5.9 (3.0 to 50.0). In the updated review, opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various validated questionnaires. Constipation was the most common adverse event (34% opioid versus 9% placebo: number needed to treat for an additional harmful outcome (NNTH) 4.0; 95% CI 3.0 to 5.6), followed by drowsiness (29% opioid versus 14% placebo: NNTH 7.1; 95% CI 4.0 to 33.3), nausea (27% opioid versus 9% placebo: NNTH 6.3; 95% CI 4.0 to 12.5), dizziness (22% opioid versus 8% placebo: NNTH 7.1; 95% CI 5.6 to 10.0), and vomiting (12% opioid versus 4% placebo: NNTH 12.5; 95% CI 6.7 to 100.0). More participants withdrew from opioid treatment due to adverse events (13%) than from placebo (4%) (NNTH 12.5; 95% CI 8.3 to 25.0). Conversely, more participants receiving placebo withdrew due to lack of efficacy (12%) versus (2%) receiving opioids (NNTH ‐11.1; 95% CI ‐20.0 to ‐8.3).

Authors' conclusions

Since the last version of this review, new studies were found providing additional information. Data were reanalyzed but the results did not alter any of our previously published conclusions. Short‐term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate‐term studies demonstrated significant efficacy of opioids over placebo, but these results are likely to be subject to significant bias because of small size, short duration, and potentially inadequate handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainty.  Reported adverse events of opioids were common but not life‐threatening. Further randomized controlled trials are needed to establish unbiased estimates of long‐term efficacy, safety (including addiction potential), and effects on quality of life.

Author(s)

Ewan D McNicol, Ayelet Midbari, Elon Eisenberg

Abstract

Plain language summary

Opioids for neuropathic pain

Neuropathic pain is pain caused by nerve damage. It is often difficult to diagnose and treat. The use of opioids (strong pain killers such as morphine) to treat neuropathic pain is controversial owing to concerns about addiction and beliefs that this type of pain does not always respond well to opioids. The review looked at short‐term studies lasting less than a day and intermediate‐term trials lasting from several days to 12 weeks. The 31 studies found involved 1237 people with neuropathic pain; most studies were small.

Short‐term studies produced mixed results, with just over half indicating that opioids might be better than a placebo. While intermediate‐term studies all indicated that opioids were better than placebo, most studies were small, most were short, and none used methods known to be unbiased. All these features are likely to make effects of opioids look better in clinical trials than they are in clinical practice. We cannot say whether opioids are better than placebo for neuropathic pain over the long term. Side effects such as constipation, nausea, dizziness, and drowsiness were common, but not life‐threatening.

Author(s)

Ewan D McNicol, Ayelet Midbari, Elon Eisenberg

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Short‐term studies provided only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate‐term studies demonstrated significant efficacy of opioids over placebo, but these results are likely to be subject to significant bias because of small size, short duration, and unclear, potentially inadequate methods for handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainty. The difference in outcomes between short‐term and intermediate‐term opioid studies does not support the use of short‐term opioid administration as a predictive tool to decide whether to initiate a trial of opioid therapy. Although our review demonstrated clinically significant efficacy of opioids and an increase in the incidence of commonly‐reported side effects in the intermediate term for neuropathic pain, the participants in the included studies may not reflect those commonly seen in practice. Therefore, issues such as rare but serious adverse events, abuse of medication, or conversely, non‐compliance due to participants' unwillingness to tolerate side effects may not be accurately reflected in our results. Clinicians may be required to assess persons' suitability for a trial of opioid therapy and to monitor progress more rigorously than they would for other pharmacological treatments.

Implications for research 

Our updated and revised meta‐analysis takes the necessary step of showing efficacy for spontaneous pain during opioid treatment for up to three months. A goal of future studies in this area should be to evaluate the true efficacy of opioids for neuropathic pain by means of trials with wider dose ranges rather than fixed‐dose studies. In addition, further RCTs assessing longer‐term efficacy, safety (including addiction potential), and improved quality of life should be undertaken before the value of opioids for management of neuropathic pain is finally established.

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